| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to evaluate the safety and tolerability of 2 dosages of GW642444H (100 and 400mcg administered once-daily for 2 weeks) versus salmeterol and placebo in subjects with moderate COPD. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to evaluate the PD profile of GW642444H in subjects with moderate COPD (including extra-pulmonary effects), the systemic PK profile of GW642444, α-phenylcinnamic acid (CC12189 - the counterion of GW642444H), the metabolites GW630200 and GSK 932009 and salmeterol following GW642444H (100 and 400mcg) or salmeterol (50 mcg) administration and the systemic exposure-response relationship. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects who give their signed written informed consent to participate.
2. Male subjects or female subjects of non child bearing potential (i.e. post-menopausal or surgically sterile) ≥40 years of age at screening (Visit 1).
Post-menopausal females are defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. However if indicated this should be confirmed by estradiol and FSH levels consistent with menopause (according to laboratory ranges) at screening (Visit 1).
Surgically sterile females are defined as those with a documented (medical report verification) hysterectomy and/or bilateral oophorectomy or Tubal Ligation
3. COPD Diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society [Celli, 2004]:
COPD is a preventable and treatable disease characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.
4. Tobacco Use: Subjects with a current or prior history of >10 pack-years of cigarette smoking at screening (Visit 1).
5. Severity of Disease:
Subjects who conform to the GOLD severity classification for Stage II disease in terms of post-bronchodilator spirometry (either confirmed within 3 months of Screening Visit 1 or at Screening Visit 1) :
• Subjects with a measured post-salbutamol FEV1/FVC ratio of ≤0.70
• Subjects with a measured post-salbutamol FEV150% and<80% of predicted normal according to Crapo et al. [Crapo, 1981]
A correction factor of 0.88 will be used in this study to determine Crapo-predicted values of FEV1 for people of African ethnic origin [American Thoracic Society, 1991].
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| E.4 | Principal exclusion criteria |
1. Women who are pregnant or lactating or of child bearing potential.
2. Primary diagnosis of asthma. (Subjects with a prior history of asthma are eligible if COPD is currently their primary diagnosis).
3. α-1 antitrypsin deficiency as the underlying cause of COPD.
4. Active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung disease or other active pulmonary disease.
5. Lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
6. Positive Hepatitis B surface antigen or positive hepatitis C antibody pre-study or at Screening (Visit 1).
7. Chest X-ray (or CT scan), which reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at screening if a chest X-ray or CT scan is not available within the 6 months preceding Screening (Visit 1).
8. Poorly controlled COPD.
9. Clinically significant cardiovascular, neurological, psychiatric, renal, immunological, endocrine or haematological abnormalities that are uncontrolled.
10. Blood potassium level <3.0mmol/L at Screening (Visit 1)
11. A mean QTc(B) value at screening (Visit 1) >430 msec (male) / >450 msec (female), a mean PR interval outside the range 120-210 msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave).
12. Any of the following abnormalities, identified on any of the resting 12-lead ECG at screening (Visit 1):
Ventricular rate <40 beats per minute PR interval >240 msec
Evidence of second or third degree atrioventricular (AV) block
Pathological Q waves (>40 msec depth greater than 0.04–0.05 mV)
Evidence of frequent supraventricular or ventricular ectopics, or arrhythmias
ST-T wave abnormalities, with the exception of "early repolarisation" which is acceptable
Right or left complete bundle branch block
13. History of elevated supine blood pressure or a mean supine blood pressure equal to or higher than 150/90 mmHg at screening (Visit 1).
14. Mean heart rate outside the range 40 – 90 beats per minute (bpm) at screening (Visit 1).
15. Carcinoma that has not been in complete remission for at least 5 years.
Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma would not be excluded if the subject was considered cured in less than 5 years since diagnosis.
16. History of hypersensitivity to any beta-agonist or to ipratropium bromide. In addition patients with a history of milk protein allergy would also be excluded.
17. Known or suspected history of alcohol or drug abuse within the last 2 years.
18. Unable to withhold their rescue medication for the 6 hour period required prior to spirometry testing at each study visit would be ineligible for the study.
19. The following medications listed below must not have been used prior to Screening (Visit 1) for the required interval indicated and not taken during the Run-in:
Medication Time Interval
Inhaled steroids at doses of > 1000mcg/day FP equivalent 6 weeks
Oral corticosteroids 8 weeks
Theophyllines 48 hours
Salmeterol and other long-acting beta-agonists 48 hours
Oral leukotriene inhibitors 48 hours
Inhaled sodium cromoglycate or nedocromil sodium 48 hours
Ipratropium/albuterol combination product 6 hours
Inhaled short acting beta-agonists 6 hours
Oral beta2-agonists 48 hours
Inhaled LABA/ICS combination products 48 hours
Tiotropium 2 weeks
Systemic, parenteral or depot corticosteroids 8 weeks
P-glycoprotein inhibitors 6 weeks
Cytochrome P 3A4 inhibitors 6 weeks
20. Treatment with diuretics, tricyclic antidepressants, Monoamine Oxidase Inhibitors, or beta-adrenergic antagonist
21. Treatment with long-term oxygen therapy (LTOT).
22. Requirement for nocturnal positive pressure for sleep apnoea.
23. Participation in the acute phase of a Pulmonary Rehabilitation Programme within 4 weeks prior to Visit 1 (Screening) or who will enter the acute phase of a Pulmonary Rehabilitation Programme during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation programme are not excluded.
24. Receipt of an investigational drug within 30 days of entry into this study (Visit 1), or within 5 drug half-lives of the investigational drug (whichever is longer).
25. Receipt of the investigational drug GW642444 in previous studies.
26. Unable to comply with study procedures.
27. Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participation in this study.
28. History of psychiatric disease, intellectual deficiency, poor motivation, substance abuse, (including drug and alcohol), or other conditions, which will limit the validity of informed consent to participate in the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The endpoints used to assess safety, tolerability and PD will be:
• Incidence of Adverse Events (AEs) reported prior to, throughout and after the 2-week treatment period as recorded by subjects on daily record cards (DRCs) and investigators (during clinic assessments).
• Summary measures for Heart Rate (HR) and Blood Pressure (BP), derived from Ambulatory blood pressure monitoring at Days 1, 7 and 14.
• Summary measures for QTc(F) (QT interval corrected by Fredericia's method) and QTc(B) (QT interval corrected by Bazett's method) values derived from Clinic visit 12-lead ECGs recorded at several time points at Days 1 and 2, 7 and 8 and, 14 and 15.
• Summary measures for Clinic visit FEV1 recorded at several time points at Days 1 and 2, 7 and 8 and 14 and 15.
• Summary measures for QTc(F) and QTc(B), premature ventricular beats, premature supraventricular beats and ventricular runs derived from 3-lead Holter ECG monitoring at Days 1, 7 and 14.
• PEFR (AM and PM) and use of rescue medication during run-in, treatment and follow-up periods as recorded by subjects on DRCs.
• Change in haematological and clinical chemistry parameters from baseline, after 1 and 2 weeks treatment.
• Summary measures of fasting glucose and potassium at several time points at Days 1 and 2, 7 and 8, and 14 and 15.
The PK parameters for derived GW642444, its counterion, metabolites and salmeterol will also be assessed.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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